The therapy of lung disease often relies on inhaled medications. Bronchodilators have are widely employed in the treatment of asthma. Inhaled aerosolized antiviral agents are employed in the treatment of infectious diseases. Although most inhaled medications are given for their local effect, there is much recent interest in aerosol delivery of medications for systemic absorption. Inhaled drugs, in the form of very small dry powder particles, may be rapidly and directly absorbed into the blood stream. Thus, for example, proteins and peptides may be self-administered rather than administered by injection.
The list of drugs currently under investigation for inhalation delivery is quite extensive. Aerosolized insulin for diabetes is anticipated to become a major application of inhalation therapy.
Most large organic molecules, including proteins and peptides, are denatured by stomach acid when ingested. Absorption in the peripheral parts of the respiratory system overcomes this problem. Thus, the physician has means to provide the patient with a technique whereby the patient may self-administer large molecule medicaments without injection. The value of inhalation therapy in administering insulin, for example, is obvious.
Prior to the development of dry powder inhalers, most inhalation therapies employed pressurized chlorofluorocarbon propellants to disperse drugs. Environmental concern relating to CFC destruction of the earth""s ozone layer has reduced the utility of this approach.
Dry powder inhalers for pulmonary drug delivery require dose levels that range from 25 micrograms to over 1,000 micrograms. Powder particle mean diameters of between 0.5 and 5.0 microns are required to provide effective deposition within the lung since larger particles tend to deposit in upper airways without any useful absorption to the circulatory system.
It is difficult to provide metered doses within the required tolerances at the 25 to 250 microgram levels. High-speed weighing systems are generally limited to dose sizes of about 5,000 micrograms or greater and thus require the active pharmaceutical be diluted with an excipient, such as lactose powder, in order to increase the total measured mass. This dilution approach is subject to limitations in mixing uniformity and the aspiration of extraneous matter by the patient.
Another approach for low dose packaging involves dispersing the active powder in a medium that is in a liquid state at room temperature. The packaging substrate is then filled or coated and the liquid evaporated leaving the powder residue on the surface of the substrate. This approach has limitations in view of potential chemical reactions between the pharmaceutical medicament and the dispersing solvent. Government agency approvals are often required for the use of this process because of these potential interaction problems.
Yet another approach for low dose packaging involves the electrostatic precipitation of aerosolized medicament onto the surface of the medicament package. Abrams et al, U.S. Pat. No. 5,699,649, describe a system employing an endless belt that is charged, developed with an aerosolized powder, and the powder image then transferred to the package. The direct electrostatic precipitation of aerosolized powder is disclosed in Pletcher, U.S. Pat. No. 5,669,973. Pletcher et al, U.S. Pat. No. 5,714,007, describe an improvement in this electrostatic precipitation apparatus. These electrostatic deposition techniques require complex control equipment to accurately meter the required dosage into each package. The rate of powder deposition is also limited due to particle transit time effects and limitations in the mass density of the aerosol. Difficulties in re-aerosolizing the particles in the user""s inhaler, because of the large electrostatic forces on the charged particles may also be significant.
The present invention provides a cost-effective method for filling unit dose packages with accurate masses of fine powder medicament. In addition, the invention provides a simple direct method for packaging very small doses of fine powders at high production rates and with uniform consistency. The invention provides for deposition onto or into a wide variety of package substrates. While employing electrostatic precipitation of an aerosol, the process does not lead to high levels of electrostatic powder cohesion.
The invention provides a process that intermittently or continuously introduces a pre-weighed mass fine powder into an aerosolization chamber. The dry powder is aerosolized and, in one preferred method, the aerosol powder charged. Charged powder is then electrostatically deposited into or onto unit dose package substrates as these packages are sequentially moved through the deposition region. The packages are arranged in a continuous line either around the circumference of a circular package transport or in a continuous line on the surface of an endless belt. As each package traverses the precipitation region, a small amount of powder is deposited. The number of packages, the package velocity and the aerosol deposition rate are selected so that a large number of passes are required to fill each package to the required dose level. It is this continuous sampling, or time division sampling (TDS), that very uniformly divides the pre-determined quantity of powder uniformly among the many packages.
Alternately, the packages may be filled using gravity settling.
The method of the invention comprises the steps of:
a. introducing a known weight of fine powder into an aerosolization chamber
b. providing a controlled flow rate of gas
c. adding the known weight of powder into the air stream at a controlled rate to form a low density aerosol form a low density aerosol,
d. providing an endless array of powder packages disposed to move sequentially through the deposition zone
e. adjusting process parameters so that a large number of passes are required to fill each package to the desired dose level
f. recycling the powder packages until all of the powder is consumed
g. removing the now filled packages and replacing with unfilled packages